Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun. 2024 Jul 12;15(1):5859. doi: 10.1038/s41467-024-49905-7.
Signal-induced transcriptional programs regulate critical biological processes through the precise spatiotemporal activation of Immediate Early Genes (IEGs); however, the mechanisms of transcription induction remain poorly understood. By combining an acute depletion system with several genomics approaches to interrogate synchronized, temporal transcription, we reveal that KAP1/TRIM28 is a first responder that fulfills the temporal and heightened transcriptional demand of IEGs. Acute KAP1 loss triggers an increase in RNA polymerase II elongation kinetics during early stimulation time points. This elongation defect derails the normal progression through the transcriptional cycle during late stimulation time points, ultimately leading to decreased recruitment of the transcription apparatus for re-initiation thereby dampening IEGs transcriptional output. Collectively, KAP1 plays a counterintuitive role by negatively regulating transcription elongation to support full activation across multiple transcription cycles of genes critical for cell physiology and organismal functions.
信号诱导的转录程序通过精确的瞬时早期基因（IEG）的时空激活来调节关键的生物过程；然而，转录诱导的机制仍知之甚少。通过将急性耗竭系统与几种基因组学方法相结合，来探究同步、时空调控的转录，我们揭示了 KAP1/TRIM28 是一个快速反应者，它满足了 IEG 对时空和更高转录需求。急性 KAP1 的缺失会在早期刺激时间点触发 RNA 聚合酶 II 延伸动力学的增加。这种延伸缺陷会破坏在晚期刺激时间点通过转录周期的正常进展，最终导致转录装置重新起始的募集减少，从而抑制 IEG 的转录输出。总的来说，KAP1 通过负调控转录延伸来发挥反直觉的作用，以支持对细胞生理学和生物体功能至关重要的多个转录循环的基因的完全激活。
